6

Findings and Recommendations

It has been more than 25 years since the 1990–1991 Gulf War ended. For more than 15 years, committees of the Institute of Medicine (IOM, now part of the National Academies of Sciences, Engineering, and Medicine) have systematically examined the available clinical, epidemiologic, and toxicologic information in efforts to explain the multiple health problems of veterans who served in the 1990–1991 Gulf War. Those health conditions have included a constellation of symptoms, commonly grouped under the label of Gulf War illness. In the beginning of the Gulf War and Health series, in response to legislative mandates, the reports examined health effects that might have resulted from specific exposures to agents such as depleted uranium (DU), pyridostigmine bromide (PB), vaccines, nerve agents (e.g., sarin), insecticides, combustion products, solvents, and infectious agents. Later reports focused more on the specific health effects that might have resulted from deployment or combat, including traumatic brain injury, deployment-related stress, and blast injuries. Two prior reports and this volume focused generally on what health effects were seen more frequently or with greater severity in veterans who had deployed to the Persian Gulf region compared with veterans who had been in the military during the war but had not deployed to the Persian Gulf region or had deployed elsewhere. Conclusions from the IOM’s series of Gulf War and Health reports have provided much useful information and have informed the Department of Veterans Affairs’ (VA’s) approach to providing both treatment and compensation to veterans.

Other organizations have also called for or undertaken research related to the health of Gulf War veterans. These organizations include VA, VA Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC), and the Department of Defense (DoD) through its Congressionally Directed Medical Research Program. Between 1994 and 2014, federal funding for research on Gulf War veterans health totaled more than $500 million (VA, 2015b).

In spite of the large amount of research, there remain substantive gaps in our understanding of the health effects resulting from deployment to the 1990–1991 Gulf War, and particularly with regard to the pathophysiology of Gulf War illness. Indeed, little progress has been made so far in identifying either specific causative agents or effective treatments, and Gulf War veterans and their families continue to report concerns about the war’s health effects. In addition, the development of and treatment for the

many persistent and debilitating symptoms that afflict some Gulf War veterans has continued to confound both the veterans and their health care providers.

In this chapter, the committee summarizes its findings and conclusions reported in the previous chapters and provides recommendations on what it considered to be the most likely avenues of research that would facilitate a better understanding of the health problems associated with Gulf War deployments and their clinical management. It also provides recommendations about areas where further research is unlikely to yield important and clinically applicable gains. Although the Volume 10 committee focused on the epidemiologic literature in making its findings, it also attempted to look at the literature broadly to identify information that might provide a more comprehensive understanding of the illnesses affecting Gulf War veterans. For example, the committee considered several new and rapidly emerging areas of scientific inquiry made possible by recent advances in genetics, immunology, and neuroimaging among other diagnostic advances.

SUMMARY OF FINDINGS

In spite of a thorough literature search, the Volume 10 committee found scant evidence to warrant changes to the conclusions made by the Volume 8 committee regarding the strength of the association between deployment to the Gulf War and adverse health conditions. Thus, veterans who were deployed to the Gulf War appear to have an increased risk for mental health disorders such as posttraumatic stress disorder (PTSD), generalized anxiety disorder, depression, and substance abuse, as well as Gulf War illness, chronic fatigue syndrome, and functional gastrointestinal conditions. Indeed, the constellation of symptoms and symptom clusters referred to as Gulf War illness (e.g., fatigue, muscle and joint pain, and cognitive problems) is the signature adverse health condition of having served in the Persian Gulf region. Multiple studies found that some Gulf War veterans, regardless of their country of origin and their different deployment-related exposures, have persistent, debilitating, and varying symptoms of Gulf War illness.

For several conditions only one study, or in some cases no studies, were of sufficient quality to meet the criteria for a primary study (see Chapter 2 for a description of the criteria for primary and secondary studies). For health conditions for which new evidence was available, the data tended to support conclusions that generally were in accordance with those of prior Gulf War and Health committees. The conclusions of the Volume 10 committee are presented in Box 6-1.

Many of the Gulf War and Health reports emphasized the lack of information, and especially exposure information, on which to base definitive conclusions regarding the strength of the association between serving in the Gulf region and given health effects, particularly those conditions that have a long latency period. The lack of specific individual exposure information is not unexpected in wartime situations, but it nonetheless limits the ability to draw conclusions about observed health effects. Importantly, this committee finds no reason to believe that additional or better information about veteran exposures will ever become available, which at this point in time materially influences what further investigations are reasonable to pursue.

Although the committee considered the literature for all health conditions reported in Gulf War veterans without preconceived ideas about what those conditions might be, the committee’s statement of task required it to pay particular attention to several specific health outcomes: neurologic outcomes (e.g., Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and migraines), cancer (brain and lung cancer, in particular), and chronic multisymptom illness (called Gulf War illness in this report). Those health outcomes were discussed in detail in Chapter 4 and are summarized briefly in the following sections. These are followed by additional recommendations related to considerations

of exposures and health effects; sex-specific, race and ethnicity-specific effects; and future research directions for Gulf War illness.

GULF WAR ILLNESS

The Volume 10 committee’s statement of task asked it to comprehensively review, evaluate, and summarize the available scientific and medical literature regarding chronic multisymptom illness that is commonly known as Gulf War illness. In spite of more than two decades of studies to help define, diagnose, determine its cause, and treat the multitude of symptoms that characterize Gulf War illness, little progress has been made in elucidating the pathophysiologic mechanisms that underlie the condition, the exposures that may have caused it, or treatments that are generally effective for veterans who suffer from it. The Volume 4 committee indicated that deployed veterans suffer from more signs and symptoms (e.g., headache, joint and back pain, fatigue and sleep problems, and cognitive dysfunction) than nondeployed veterans. The increased prevalence of diverse symptoms has been seen in Gulf War veterans from the United States as well as several of the coalition countries (e.g., Australia, Canada, the United Kingdom), as well as in Danish veterans who served as peacekeepers after the conflict ended. The literature described in Volume 8 and in this volume provides further support for the conclusion that there is sufficient evidence of an association between deployment to the Gulf War and Gulf War illness. It must be noted, however, that some nondeployed veterans have symptoms that mirror Gulf War illness in spite of never having served in the Gulf region.

Over the past 25 years, many research efforts have been conducted in attempts to further understand Gulf War illness, including follow-up surveys of large samples of veterans to assess the prevalence and incidence of symptoms, clinical examinations of small groups of ill veterans, and animal toxicologic studies. Specialized studies have been conducted on various aspects of Gulf War illness, including neurologic, autonomic, and immune function; genetic susceptibility; behavior; and quality of life. Chapter 3 described the many Gulf War veteran cohorts that have been studied and the numerous derivative studies on those cohorts that have looked at the prevalence and incidence of a variety of health conditions. Other derivative studies have attempted to identify biological markers of disease and the interactions between health conditions in these veterans (e.g., Gulf War illness and obesity). Results from many of these studies have been summarized in Chapter 4. Because veterans’ exposures were not uniform, some researchers have suggested that any associations have been obscured by investigations that look at veterans as a whole rather than by subgroups (White et al., 2015). While, in theory, analyses by subgroups of veterans defined by exposure, location, or other proxy might provide additional information, the available studies do not conduct such analyses nor is it likely that subgroups with known exposures can be reliably defined because there is no good exposure information on which to define them.

It is evident that Gulf War illness is the predominant health concern for many veterans, but as highlighted in this report and others (IOM, 2015), Gulf War illness is by no means an easily diagnosed condition. It presents with diverse symptom clusters, many of which overlap with other health conditions such as chronic fatigue syndrome, neurodegenerative disorders, and musculoskeletal problems, and there are multiple case definitions of it. In 2015, the IOM addressed the issue of a case definition of Gulf War illness and recommended that researchers use either the Centers for Disease Control and Prevention definition or the Kansas definition depending on the intent of the research (see the section on Gulf War illness in Chapter 4 for more information on the case definitions).

Although there has been a substantial body and a broad basis of research on Gulf War veterans, there are still substantial gaps and limitations in the body of evidence regarding the health effects of deployment to the Gulf War, and Gulf War illness in particular. This committee echoes the concerns

stated in earlier volumes: why do some veterans have a multitude of symptoms of Gulf War illness whereas others have only a few symptoms, and other veterans who served in the same area with seemingly similar exposures remain entirely without symptoms? Why do some veterans who were not on the ground in the Persian Gulf region such as the majority of Australian forces, or who served after the war as peacekeepers, such as the Danish forces, or who were not near the Khamisiyah demolition area such as the British forces, also experience symptoms of Gulf War illness? Unfortunately, given the inconsistency and lack of replication of results and the often limited research methods, there is little reliable information on which to base a comprehensive view of Gulf War illness. Furthermore, varying definitions of Gulf War illness add to the confusion regarding its study and makes replicating results and meta-analyses across studies problematic.

Although the committee determined that Gulf War illness is not a psychosomatic condition, a continuing problem with studying Gulf War illness is that most of the studies have excluded important psychophysiological aspects of the illness with regard to both diagnosis and treatment, in spite of veterans identifying symptoms such as chronic pain and sleep disturbances that may be amenable to psychophysiological therapies, alone or in conjunction with other treatments. Based on available research data, it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war. The Gulf War and Health committee that assessed the effects of deployment-related stress on the physiological and psychological health of Gulf War veterans (IOM, 2008b) found that such stress, which can arise from many different stimuli, such as hearing chemical alarms to seeing dead bodies or using pesticides to keep away sand fleas, can result in short-term and long-term physical reactions. That committee stated the following:

The Volume 10 committee emphasizes that the deployment-related chronic health effects include many of those that characterize Gulf War illness.

Emerging diagnostic technologies and personalized approaches to medical care offer promise for allowing sufficiently powered research on the diagnosis and treatment of Gulf War illness. As stated by the Volume 8 committee (IOM, 2010) and concurred with by the Volume 10 committee:

For example, it may be productive to conduct transcriptomic studies if the study protocols had methodological enhancements such as expanding the size of the study cohorts so the studies were robustly powered; using distinct discovery and replication cohorts, again each appropriately powered; using RNAseq methods which allow for analysis of sequences and numbers of all coding and noncoding RNA transcripts in an unbiased manner; using appropriately chosen control groups; and using appropriate bioinformatics tools to discern specific disease pathways.

Many efforts have been directed at linking Gulf War illness to one or more exposures that occurred in the Persian Gulf region using animal models and mixtures of chemical such as PB, DEET, and chlorpyrifos (see Chapter 5). Although animal studies have suggested some physiological and structural alterations in response to the chemical exposures that Gulf War veterans might have experienced while deployed, they have typically examined isolated symptoms of Gulf War illness rather than the constellation of symptoms reported by Gulf War veterans. Furthermore, the animal studies conducted to date have provided inconsistent results. Thus, in general, animal studies that attempt to mimic Gulf War illness have provided little in the way of helpful information because it is difficult to establish experimental exposures that replicate those experienced by Gulf War veterans during deployment when actual exposures are uncertain. Therefore, the committee concludes that although the existence of an animal model would be advantageous for identifying and evaluating treatment strategies for Gulf War illness, it cautions that developing such an animal model for Gulf War illness is not possible, given researchers’ inability to realistically determine the exposures associated with Gulf War service, let alone the frequency, duration, or dose of those exposures, or the effect of multiple exposures.

In consideration of these things, the committee makes the following recommendations:

Recommendation: Any future studies of Gulf War illness should recognize the connections and complex relationships between brain and physical functioning and should not exclude any aspect of the illness with regard to improving its diagnosis and treatment.

Recommendation: The Department of Veterans Affairs and the Department of Defense should develop a joint and cohesive strategy on incorporating emerging diagnostic technologies and personalized approaches to medical care into sufficiently powered future research to inform studies of Gulf War illness and related health conditions.

NEUROLOGICAL CONDITIONS

The Volume 10 committee was specifically tasked with assessing the association between deployment to the Persian Gulf region and the prevalence of neurologic conditions, particularly Parkinson’s disease, multiple sclerosis, ALS, and migraines. As described in Chapter 4, the committee considered each of these neurologic conditions separately.

The new evidence for multiple sclerosis, combined with that from Volume 8, suggests that in spite of studies which looked specifically for the disease in Gulf War veterans, there is limited/suggestive evidence of no association between deployment to the Gulf War and multiple sclerosis.

ALS is the only neurologic disease for which both this committee and the Volume 8 committee found limited/suggestive evidence of an association with deployment to the Gulf War. A previous IOM committee (IOM, 2006a) also noted that in the early years after the war, there was limited/suggestive evidence of an increase in the incidence of ALS in deployed veterans. Given that ALS and other neurodegenerative diseases are age-dependent, further surveillance in this population is warranted. Although Gulf War deployment was associated with increased risk of developing ALS and increased ALS severity,

no association with ALS mortality (a uniformly fatal disease) was found. Thus, more research is warranted to clarify potential associations between ALS and Gulf War deployment.

The committee did not find that sufficient time has elapsed to assess whether any deployment-related exposures might have increased the occurrence of other neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and related disorders. Thus, the committee found that there continues to be inadequate or insufficient evidence to indicate any association between deployment to the Gulf War and neurodegenerative diseases other than ALS.

A conclusion of inadequate or insufficient evidence was also reached for the association of deployment to the Gulf War with migraines, which was considered specifically for the first time in this volume. The committee notes, however, that many of the health assessments on Gulf War veterans explored the presence of headaches but did not specifically ask about migraines. Therefore, the committee cautions that the occurrence of migraines in Gulf War veterans may be imprecisely established, in light of the uncertainty of subjective reports.

Given the substantial growth in the field of genetics and epigenetics as it relates to complex illness, some diseases studied relative to Gulf War deployment might be further informed by inclusion of genetic research aims. Specifically, in those diseases in which there is a highly penetrant, frequently present, and feasibly measured genetic risk marker, inclusion of these factors should be strongly considered when exploring the relationships between Gulf War deployment and subsequent disease. Among the relevant examples are the neurodegenerative diseases, which the committee anticipates will become more relevant for study over time, given their typically long latency and an aging veteran population. It will be of critical importance, however, that studies to identify novel genetic risk factors be robustly powered and appropriately designed to include both discovery and replication data. Until these approaches are considered, the committee anticipates substantial difficulty in better understanding the complexities associated with these neurodegenerative disorders in Gulf War veterans.

Recommendation: The Department of Veterans Affairs should continue to conduct follow-up assessments of Gulf War veterans for neurodegenerative diseases that have long latencies and are associated with aging; these include amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease.

LUNG AND BRAIN CANCER

The Volumes 8 and 10 committees were asked to specifically consider whether Gulf War veterans were at increased risk for developing any form of brain cancer, a relatively rare cancer. The Volume 4 committee described one mortality study of Gulf War veterans that found an increased risk of dying from brain cancer in deployed veterans through 2000. The increased risk was associated with being exposed to the nerve agents at Khamisiyah with a dose–response that corresponded to the duration of exposure (0 vs 1 vs ≥ 2 days). That committee noted that brain cancer typically has a latency period of 10–20 years and thus the increase seen at about 9 years after exposure needed to be interpreted with caution. The Volume 8 committee found one additional study of brain cancer that was a 4-year follow-up to the earlier mortality study (Barth et al., 2009). Barth et al. (2009) failed to show an increased risk of dying from brain cancer in the deployed vs nondeployed veterans, but did report that 2 or more days of exposure to nerve agents at Khamisiyah and exposure to smoke from oil-well fires were both significantly associated with an increased risk of brain cancer mortality. Exposures to the nerve agents and smoke from the oil-well fires, however, were both determined by modeling, and GAO (2004) reported that the modeling had serious limitations. These model limitations make it impossible to determine individual

service member exposures and therefore to link the modeled exposures to health outcomes. The four new studies identified by the Volume 10 committee found no statistically significant increased risk of brain cancer in Australian or U.S. Gulf War veterans compared with their nondeployed counterparts, although the power of the Australian study to detect rare cancers such as brain cancer was low. Overall, the studies indicate that the evidence for an association between deployment to the Gulf War and brain cancer is inadequate/insufficient.

The Volumes 4 and 8 committees found no evidence to indicate that Gulf War veterans were at increased risk for lung cancer in the approximately 10–15 years after the war, but the Volume 10 committee emphasizes that lung cancer may have a latency of longer than 15 years and that studies to date are not sufficient to exclude a higher risk of lung cancer among Gulf War veterans. This committee reviewed one large study of U.S. Gulf War veterans that found an increased incidence of lung cancer based on state and VA cancer registry data from 1991 to 2006 for deployed vs nondeployed veterans, but neither veteran group had a greater risk when compared with the general population. Importantly, as the committee noted in Chapter 4, this new study provided no information on smoking behavior among the veterans. Because about 90% of lung cancer in the United States is related to smoking, the lack of smoking information materially precludes interpretation of the study’s finding. In spite of this limitation, the committee found the pooling of data across registries to be a good approach for increasing the sample size and thus the power of the study.

In summary, the Volume 10 committee finds that the evidence continues to be inadequate/insufficient to determine whether deployed Gulf War veterans are at increased risk of developing any cancer, including lung cancer and brain cancer. The relative rarity of cancers such as brain cancer argues for larger studies with adcancer equate statistical power. This may require pooling data where feasible and the use of a variety of data sources such as state cancer registries.

Recommendation: The Department of Veterans Affairs should conduct further assessments of cancer incidence, prevalence, and mortality because of the long latency of some cancers. Such studies should maximize the use of cancer registries and other relevant sources, data, and approaches, and should have sufficient sample sizes to account for relatively rare cancers. These studies should also be able to report sex-specific and race/ethnicity-specific information.

OTHER HEALTH CONDITIONS

In contrast to cancer, the committee finds that sufficient time has elapsed to determine that Gulf War veterans do not have an increased incidence of circulatory, hematologic, respiratory, musculoskeletal, structural gastrointestinal, genitourinary, reproductive, and chronic skin conditions.

The committee is also cognizant of the fact that as Gulf War veterans age, it will be more difficult to differentiate the effects of deployment from the natural effects of aging on morbidity and mortality.

The committee finds that the association of service in the Gulf War with PTSD, anxiety disorders, substance abuse, and depression is now well established and further studies to assess whether there is an association are not warranted.

There are no data suggesting delayed effects of Gulf War exposures that might have arisen from such chemicals as nerve agents or PB. Furthermore, the serum half-lives of chemicals such as nerve agents and PB are not consistent with their long-term retention in the body; such retention would be necessary to cause adverse health effects years after exposure (IOM, 2000, 2004). Thus, the committee finds that it is not reasonable to expect new onset disease, with the exception of diseases with especially long latency periods such as some types of cancer.

Recommendation: Further studies to assess the incidence and prevalence of circulatory, hematologic, respiratory, musculoskeletal, structural gastrointestinal, genitourinary, reproductive, endocrine and metabolic, chronic skin, and mental health conditions due to deployment in the Gulf War should not be undertaken. Rather, future research related to these conditions should focus on ensuring that Gulf War veterans with them receive timely and effective treatment.

EXPOSURE ASSESSMENTS

Chief among the concerns of the Gulf War and Health committees, including this committee, has been the lack of reliable exposure information about the environmental and occupational agents in the Persian Gulf region. Beginning with Volume 1, IOM committees have noted that environmental sampling was not conducted during the war, making it virtually impossible to know the particular agents that were present, let alone the potential frequency, intensity, or duration of individual exposures to such agents. Furthermore, as noted in Chapter 2, exposures were neither isolated nor due to single agents; veterans were typically exposed to multiple agents in varying combinations of varying duration and intensity during deployments. Record keeping for exposures such as vaccines was poor, some veterans self-administered agents (e.g., insecticides for sand fleas and PB when chemical alarms sounded), and some exposures were ubiquitous (e.g., smoke from oil-well fires, high ambient temperatures, and sand). Many veterans continue to be concerned about the health effects stemming from possible exposure to sarin and cyclosarin after the demolition of munitions at Khamisiyah. Modeling efforts to identify veterans who may have been exposed to the nerve agents have proven to be problematic and not reassuring to the thousands of veterans who continue to experience unexplained symptoms. Both false positive (self-reporting exposure but no exposure occurred) and false negative (self-reporting no exposure when an exposure actually occurred but the veteran was not aware of it) reporting biases are possible with respect to exposure.

Even today, some researchers continue to try to assess veterans’ exposures using surveys. As stated by the Volume 8 committee and strongly endorsed by this committee, “At almost 2[5] years after the war, it is difficult, if not impossible, to reconstruct the exposures to which the veterans were subjected in theater.” Given the lack of objective exposure information at an individual level (except for DU), the committee concludes that further studies aimed at determining cause-and-effect relationships between Gulf War exposures and health effects seen in Gulf War veterans are unlikely to produce useful information. Although military records for veterans of coalition countries may have more information on administration of vaccines and other medical procedures, the applicability of such data to U.S. Gulf War forces is uncertain.

Although many animal studies have attempted to simulate exposure scenarios that mimic possible chemical exposures that occurred during the Gulf War, this has proven to be difficult and the test mixtures and doses are not necessarily representative of the real-world exposures experienced by veterans during deployment. For example, as discussed in Chapter 5, some researchers have developed exposure scenarios for animal models of Gulf War illness that have generally included some combination of sarin, DEET, permethrin, paraoxon, and chlorpyrifos, with a physical stressor such as heat or forced swimming. How accurately these exposures simulate the exposures in the Persian Gulf region is not possible to determine. Furthermore, common stressors experienced by the veterans such as exposure to combustion products, diesel fumes, solvents, and other pesticides are not included in these animal models. Overall, while these studies may be interesting, or even intriguing, and may eventually be helpful in identifying markers of illness or treatment, the applicability of those exposures to what actually occurred in the Gulf War is uncertain.

One exception to the inability to reliably determine Gulf War exposures is DU. The surveillance program at the University of Maryland that is monitoring the long-term health effects of embedded DU in a group of Gulf War veterans (i.e., studies by McDiarmid and colleagues) is the only instance of a successful exposure assessment in veterans because DU can be measured in human tissue over time.

For future conflicts, collecting exposure information before, during the deployments, and afterward, preferably using environmental and individual monitoring devices and military records (both health and administrative) to capture such information as vaccines, troop location, and toxicant concentrations, would make the data less subject to recall bias and permit a more accurate assessment of actual exposures.

Recommendation: Without definitive and verifiable individual veteran exposure information, further studies to determine cause-and-effect relationships between Gulf War exposures and health conditions seen in Gulf War veterans should not be undertaken.

SEX, RACE, AND ETHNICITY

An unprecedented number of women deployed to the Gulf War (almost 50,000), and this was the first war in which women were deployed to combat zones, but few data are available on the health of those women. And while the proportion of women who served in the Gulf War was less than the number of women who have served in the conflicts in Iraq and Afghanistan, it is nonetheless important to assess and report on their health status so that health patterns over time and historical exposures can be understood and be used to improve women veterans’ health and potentially avoid problems in the future.

As female Gulf War veterans age, it is important to track morbidity and mortality trends among this not insignificant number of women. The Volume 8 committee noted that “Female Gulf War veterans experienced many of the exposures and stressors that male Gulf War veterans experienced while deployed to the Persian Gulf region in 1990–1991.” And although women were excluded from combat roles per se, they were deployed to combat zones. They were more likely to have experienced sexual harassment or assault while deployed than men.

Women may have different responses to stress and other exposures than men and, thus, may have different health consequences. For example, three out of four people who have migraines are women, and women tend to have more severe migraines (womenshealth.gov, accessed November 12, 2015). Women also have different risk profiles for cardiovascular disease, musculoskeletal disorders, and some cancers.

In a similar manner, health risks for race and ethnic minority veterans may also be different. Genetic risks for some diseases vary across race and ethnicities, for example, blacks are at greater risk for some genetic causes of ALS. and for heart disease than whites. Even among Gulf War veterans, racial differences are seen. For example, Hispanic and black Gulf War veterans reported increased rates of PTSD, major depressive disorder, and Gulf War illness (Coughlin et al., 2011b), as well as neurological conditions and multiple sclerosis (Wallin et al., 2012), compared with white Gulf War veterans.

Notwithstanding well-established differences in health conditions according to sex and race/ethnicity, few studies on Gulf War veterans specifically report outcomes for women or racial/ethnic minorities, although many veteran studies adjust for sex and race/ethnicity in their analyses. This lack of distinction is important and makes it imperative that researchers report sex- and race/ethnicity-specific outcomes, particularly in large cohorts. For example, in large studies such as the VA National Health Survey of Gulf War Veterans and Their Families, data on the health of women and race/ethnicity groups are collected, but are rarely reported as sex- or race/ethnicity-specific outcomes. Research on women’s health, including reproductive health, should seek to address stressors and exposures that women in the military

may experience. For example, new research suggests that stress exposure in young women may cause gynecologic effects that may be associated with early menopause (Bleil et al., 2012). Assessing the incidence of early menopause among female Gulf War veterans would be helpful in determining the link between deployment stress and health conditions in women and the possible need for early screening of these women for estrogen-related cancers. Overall, the committee concludes that, to date, studies of Gulf War veterans have not adequately considered sex- and race/ethnicity-specific health conditions.

Recommendation: Sex-specific and race/ethnicity-specific health conditions should be determined and reported in future studies of Gulf War veterans. In addition, selected prior studies (e.g., large cohort studies) should be reviewed to determine whether reanalysis of the data to assess for possible sex-specific and race/ethnicity-specific health conditions is feasible.

MOVING FORWARD

Beginning with Volume 1 of the Gulf War and Health series, numerous IOM committees have reviewed the literature on the health of Gulf War veterans. Although there have been some variations, generally, the results have been remarkably consistent. What is striking about this and prior Gulf War and Health committees’ findings is that the health conditions found to be associated with Gulf War deployment are primarily mental health disorders and functional medical disorders. What links these conditions is that they have no objective medical diagnostic tests and are diagnosed based on subjective symptom reporting. These associations emphasize the interconnectedness of the brain and body.

The committee concludes that it is time research efforts move forward and focus on this interconnectedness when seeking to improve treatment of veterans for Gulf War illness.

Further exploration of symptom management approaches and treatments for Gulf War illness, even in the absence of definitive etiologies, is warranted, as is the case with so many other medical conditions. Researchers have already conducted some clinical trials based on therapies that have previously shown benefits for conditions characterized by symptoms having unexplained etiologies. Therefore, Gulf War illness research should be realigned to focus on the treatment of its complex symptomatology rather than causal mechanisms. Such research should recognize the growing evidentiary base demonstrating an intricate brain–body relationship and complex relationships between brain and physical functions. For example, as noted earlier, the acute response to an exposure that causes stress (physiologic or psychologic) involves interactions among multiple organs and organ systems, including the brain, gastrointestinal tract, heart and circulatory system, liver, immune system, thyroid, adrenals and pituitary glands, gonads, bone, and skin. Acute and chronic health effects of stress on workers in diverse occupations (e.g., firefighters, bus drivers, computer operators, emergency services personnel, police officers, and nurses) have been well documented in recent years. Clearly, a stress response, such as could occur in a war zone, results in a cascade of physiologic changes that can have profound and lasting effects on multiple organ systems. To ignore available treatments that may improve the functioning of any of these organ systems is to do a disservice to our Gulf War veterans.

Recommendation: Future Gulf War research should place top priority on the identification and development of effective therapeutic interventions and management strategies for Gulf War illness. The Department of Veterans Affairs should support research to determine how such treatments can be widely disseminated and implemented in all health care settings.

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